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Gao, F., Yue, X., Yang, H., Yang, Y., Lam, S., Peng, W., and Chen, X. (2023). "Health damage and repair mechanism related to formaldehyde released from wood-based panels," BioResources 18(1), Page numbers to be added.

Abstract

Wood-based panels, which contain wood raw materials along with urea-formaldehyde (UF) or phenol-formaldehyde (PF) resins, can increase the indoor air concentration of formaldehyde. Formaldehyde can stimulate the upper respiratory mucosa and cross-linking reaction with cell proteins and DNA, and this can result in degeneration and necrosis of respiratory cells and damaged cell proliferation. Formaldehyde can induce health hazards such as nasal cancer, leukemia, and destruction of the reproductive system. Acetaldehyde dehydrogenase 5 (ADH5) in the body cooperates with Fanconi anaemia complementation group D2 (FANCD2) to quickly metabolize formaldehyde into formate and maintain the balance of endogenous formaldehyde. However, when both ADH5 and FANCD2 proteins have defects or mutations, damaged DNA repair failure and cell proliferation induce a variety of health diseases. The damage has been found in the upper respiratory area, not on distal body tissues such as liver, kidney, and bone marrow. Meanwhile epidemiological survey has not shown a positive correlation between formaldehyde and health hazards. It is recommended that the use of wood formaldehyde-based products should be reduced, and pathogenesis genes and damage repair mechanism should be studied systematically and deeply to develop gene drugs to remove excess formaldehyde and activate the damage gene repair mechanism in the future.


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Health Damage and Repair Mechanism Related to Formaldehyde Released from Wood-based Panels

Fan Gao,a,# Xiaohen Yue,a,# Hongqi Yang,a,* Yafeng Yang,a,* Su Shiung Lam,b Wanxi Peng,a and Xiangmeng Chen a,*

Wood-based panels, which contain wood raw materials along with urea-formaldehyde (UF) or phenol-formaldehyde (PF) resins, can increase the indoor air concentration of formaldehyde. Formaldehyde can stimulate the upper respiratory mucosa and cross-linking reaction with cell proteins and DNA, and this can result in degeneration and necrosis of respiratory cells and damaged cell proliferation. Formaldehyde can induce health hazards such as nasal cancer, leukemia, and destruction of the reproductive system. Acetaldehyde dehydrogenase 5 (ADH5) in the body cooperates with Fanconi anaemia complementation group D2 (FANCD2) to quickly metabolize formaldehyde into formate and maintain the balance of endogenous formaldehyde. However, when both ADH5 and FANCD2 proteins have defects or mutations, damaged DNA repair failure and cell proliferation induce a variety of health diseases. The damage has been found in the upper respiratory area, not on distal body tissues such as liver, kidney, and bone marrow. Meanwhile epidemiological survey has not shown a positive correlation between formaldehyde and health hazards. It is recommended that the use of wood formaldehyde-based products should be reduced, and pathogenesis genes and damage repair mechanism should be studied systematically and deeply to develop gene drugs to remove excess formaldehyde and activate the damage gene repair mechanism in the future.

DOI: 10.15376/biores.18.1.Gao

Keywords: Formaldehyde; Wood-based panel; Carcinogen; Health hazards; Leukemia; Gene therapeutic drugs

Contact information: a: School of Forestry, Henan Agricultural University, Zhengzhou, 450002, China; b: Pyrolysis Technology Research Group, Institute of Tropical Aquaculture and Fisheries (AKUATROP), Universiti Malaysia Terengganu, 21030 Kuala Nerus, Terengganu, Malaysia; #These authors contributed equally to this work and act as co-first authors; *Corresponding authors: yhq0373342@henau.edu.cn (Hongqi Yang); yangyafengzz@163.com (Yafeng Yang); xmchen0610@163.com (Xiangmeng Chen)

GRAPHICAL ABSTRACT

INTRODUCTION

Formaldehyde is contained in various wood bio-based products that are processed in the construction industry and light industry, such as wood raw materials/UF (urea-formaldehyde) or wood raw materials/PF (phenol-formaldehyde) (Dunky 1998; Kim et al. 2011). The annual output of woody formaldehyde bio-based products containing only formaldehyde is over 300 million m3. In addition, low-concentration formaldehyde is used for disinfection of public places, as it reduces droplet-borne diseases such as influenza and Covid-19 due to absorption on surfaces facilitating long-term disinfection (Patterson et al. 2020). However, as a ubiquitous indoor air pollutant, formaldehyde is released from formaldehyde-based products such as woody products and electronics (Quievryn and Zhitkovich 2000; Lefebvre et al. 2012; Gudmundsson et al. 2019).

In recent years, the preparation method and performance of thermoplastic adhesive wood-based panels have been improved (Lu et al. 2017). The long-term problem of formaldehyde emission can be effectively improved through improving hot pressing technology, modification of adhesives, and developments in wood-based panel post-processing technology (Basta et al. 2006; Mo et al. 2022). The use of nanotechnology materials, reduction of formaldehyde-urea molar ratio, and usage of formaldehyde scavengers can reduce free formaldehyde emissions (Costa et al. 2013; Gangi et al. 2013; Moubarik et al. 2013; Pizzi et al. 2020; Antov et al. 2021a,b,c; Bekhta et al. 2021a,b; Selakjani et al. 2021; Dorieh et al. 2022a; Dorieh et al. 2022b; Kristak et al. 2022; Kristak et al. 2022). Post-treatment techniques such as veneer and edging can also effectively reduce the formaldehyde emissions rate (Roffael 2011; Costa et al. 2013; Bekhta et al. 2018). But most of the methods cannot be industrialized, and there is no way to completely solve the free formaldehyde (Antov et al. 2022; Kristak et al. 2022). Therefore, formaldehyde emission is still one of the main disadvantages and a major source of indoor air pollution (Dorieh et al. 2022a).

Inhaling airborne formaldehyde causes irritant responses in the upper respiratory tract, including nasal cavities and alveolar epithelia (Ezratty et al. 2007). Acetaldehyde dehydrogenase in the human body quickly metabolizes exogenous formaldehyde into formate and excretes it out of the body, maintaining the balance of endogenous formaldehyde to prevent genotoxic hazards. Long-term inhalation of high concentration formaldehyde increases the risk of protein cross-linking, including amino acid and ribonucleic acids, which has irreversible effects on immunity and genetics. Formaldehyde exposure could result in degeneration and necrosis of respiratory cells, damaged cell proliferation, and cancers (Taskinen et al. 1999; Qin et al. 2020). Triggered by the reclassification of formaldehyde as a carcinogenic substance (Mantanis et al. 2018), formaldehyde-based products have declined in popularity. Therefore, the correct understanding of the mechanism of formaldehyde inhalation and metabolism, gene damage and repair, and treatment and preventive measures are important in order to treat formaldehyde pollutants effectively (Ai et al. 2019).

Sources of Indoor Formaldehyde

Formaldehyde is a ubiquitous product in nature that can be produced by high-energy carbon dioxide and water under the photooxidation of sunlight, and it is a by-product of forest fires (Kim et al. 2011). Formaldehyde is released from plant stimulants, disinfectants, and nitrogen fertilizer used in agriculture (Salthammer and Gunschera 2021). In addition, formaldehyde results from fuel combustion, tobacco smoke, and the chemical industry (Gustafson et al. 2005). Formaldehyde-based fungicides and personal care products such as shampoo and cosmetics also release formaldehyde (Abe et al. 2020; Lopez-Sanchez et al. 2021). Formaldehyde is a natural compound in many plant-based foods (Blunden et al. 1998; Dhareshwar and Stella 2008; Jung et al. 2021; Silva et al. 2021).

The main sources of indoor formaldehyde are formaldehyde-based products (Table 1), which include wood-based panels, paints, furniture, carpeting, drapery fabric, building insulation materials, and electronic products. The release period of some products is more than 3 years. The highest formaldehyde emissions appear in summer and in airtight dry spaces (Kelly et al. 1999; Wiglusz et al. 2002; Kim and Kim 2005; Kim et al. 2011).

Table 1. Formaldehyde Emission Rate of Consumer Products

Hazards of Formaldehyde Exposure

Formaldehyde is a toxic one-carbon compound having high water solubility and high reactivity; its half-life in blood is 1 to 1.5 min. Epidemiological investigation and in-depth research of formaldehyde exposure show that formaldehyde results in many kinds of health hazards. The hazardous effects of inhalation different concentrations of formaldehyde on humans and several kinds of species are shown in Table 2 (Kane and Alarie 1977; Wartew 1983).

For most people, small amounts of formaldehyde gas do not irritate eyes and nasal cavity, while short-time exposure to formaldehyde affect respiratory mucosa membrane and damage the cornea, resulting in tears and vision loss (Aerts et al. 2020). Repeated formaldehyde exposure and contact with skin may lead to development of severe dermatitis, bronchitis, and asthma with significant clinical respiratory disease, including pronounced lachrymation, pulmonary oedema, and pneumonitis (Bryson et al. 1981; Wartew 1983). In some, tolerance develops. If a large amount of formaldehyde solution is ingested accidentally, formaldehyde is rapidly metabolized into formic acid, leading to serious acidosis, causing corrosion to the upper digestive tract and ultimately death. A study of leukaemia and nasopharyngeal carcinoma of more than 50,000 professional workers of formaldehyde exposure for up to 60 years clearly shows that occupational exposure to formaldehyde was not the inducement of leukemia and nasopharyngeal carcinoma, but the proportion of patients exposed to formaldehyde is high (Coggon et al. 2003; Kathleen 2003; Golden 2011).

Acetaldehyde dehydrogenase (ADH5) in the body metabolizes formaldehyde into formate, water, and carbon dioxide, which are excreted with urine (Heck et al. 1985; Monticello et al. 1996; Barber and Donohue 1998). Though inhalation of high formaldehyde concentrations may temporarily increase the endogenous formaldehyde level, a safe level could be maintained by the metabolic mechanism (Heck et al. 1990; Dhareshwar and Stella 2008; Agathokleous and Calabrese 2021). The irritation and damage of formaldehyde is concentrated in the respiratory and digestive tracts, but long-term indoor exposure increases the risk of insomnia, headaches, nasal cancer, and leukaemia (Møller 1980; Anonymous 1981; Bernardini et al. 1981; Tatsuo et al. 1999). Preventive measures, such as opening windows for ventilation, should be taken to avoid prolonged inhalation of formaldehyde.

Table 2. Effects of Formaldehyde Exposure by Inhalation and Acute Toxicity Dose

Health Hazards Mechanisms of Formaldehyde Exposure

The hazards of formaldehyde mainly come from its effects on genetic material (Coggon et al. 2003). Formaldehyde has high reactivity, and any formaldehyde that is not metabolised can cause DNA-adducts (including DNA-protein and DNA interstrand crosslinks) (Tan et al. 2020). Formaldehyde reacts with common proteogenic amino acids and other nucleophilic amino acids at different rates through hydroxymethylation, cyclization, cross-linking or disproportionation, which have different stability and significant biochemical complexity. They play an important role in health, disease biology, and evolution (Kamps et al. 2019). The main formaldehyde cross-linking site is aminogroup (-NH2) of histone lysine, and it only reacts with free amino groups at the denaturation sites (Van et al. 1975; Vaughn 1978). When excessive formaldehyde is not metabolized, formaldehyde is cross-linked preferentially at DNA denaturation sites and causes single-strand breaks in DNA and DNA-protein cross-linking, which leads to DNA damage, DNA repair inhibition, and chromosomal mutations. Formaldehyde is mutagenic and carcinogenic in Drosophila larvae, bacteria, fungi, and rodents, and it poses a potential carcinogenic risk to humans (Grafstrom et al. 1985; Solomon et al. 1988).

In experiments using [14C]-labelled formaldehyde, 91% of the inhaled formaldehyde was metabolized in nasal mucosa, while 9% was covalently linked with DNA protein. After exposure to [14C] formaldehyde by inhalation in rats, approximately 40% was respired as 14CO2, 40% was cross-linked with macromolecules, and 20% was excreted as formate (Casanova 1989). Exogenous formaldehyde has little or no effect in distal organs such as spleen, kidney, liver, and bone marrow (Table 3) (Heck and Casanova 2004). It is a causative agent of carcinogenic genotoxicity in the nasal epithelium.

With the concentration increase of [13C]-formaldehyde, the concentration of endogenous formaldehyde gradually stabilizes, but the total formaldehyde concentration in blood does not increase (Kleinnijenhuis et al. 2013; Swenberg et al. 2013). Endogenous formaldehyde is the main source of DNA deficiency and leukemia (Yu et al. 2015). Regardless of exposure time, endogenous DNA-protein cross-linking (DPCs) are found in all examined organs. In contrast, exogenous DPCs only are present in nasal tissues and not in the distal organs, suggesting that the distal organs are less damaged by exogenous formaldehyde (Thrasher and Kilburn 2001; Duong et al. 2011).

Alcohol dehydrogenase 5 (ADH5) is a formaldehyde-decomposing enzyme in the body. ADH5 metabolizes exogenous formaldehyde into formate, thus preventing DPCs. When the gene of ADH5 is defective or mutant, exogenous formaldehyde can lead to bone marrow failure (Tan et al. 2020). If this happens, Fanconi anemia complementation group D2 (FANCD2) protein repairs DNA lesions and prevents cell proliferation, thereby preventing leukaemia, liver dysfunction, and other diseases. Detoxification also produces benign 1 C units, which maintain basic metabolism (Lucas et al. 2015; Burgos-Barragan et al. 2017; Nadalutti et al. 2021). If ADH5 and FANCD2 proteins are defective or mutant at the same time, the repair of bone marrow will fail, and many diseases will be induced by exogenous formaldehyde (Fig. 1). Thus, exogenous formaldehyde has a long-term impact on humans with gene defects in ADH5 and FANCD2. As the nasal cavity is the first to be exposed to formaldehyde, the lesions of cell proliferation and dysplasia firstly occur in the nasal cavity and involved tumor development (Nishikawa et al. 2021). The incidence of nasal tumors is the highest.

Table 3. Formation of N2-HOMe-dG Mono-Adducts and dG-Me-Cys in the Different Tissue of Rats

Fig. 1. Source of exogenous formaldehyde in body and deep hazards of lack of ADH5 and FANCD2 (Lucas et al. 2015, Creative Commons CC-BY)

Controversies of Formaldehyde Health Hazards

Formaldehyde exposure can induce obvious irritation, such as pronounced lachrymation, dizziness, loss of sense of smell, and pulmonary oedema. More importantly, it has strong and potential cytotoxicity and genetic toxicity and plays an important role in tissue carcinogenesis. Formaldehyde is a carcinogen and causative agent of human leukemia. Because formaldehyde is classified as a Group 1 carcinogen by the International Agency for Research on Cancer, there is popular worry about using woody formaldehyde bio-based products. Formaldehyde is listed as a major indoor pollutant by many countries (Chen et al. 2016). Many laws and regulations prohibit the addition of formaldehyde in food, cosmetics, and other products that are directly consumed and come into contact with the skin. Strict standards have been formulated for emissions from formaldehyde-based biopolymers in indoor and outdoor products. Excessive emission woody products are forbidden or reduced for use in indoor decoration, furniture, and other products. Although some studies have shown that the higher formaldehyde concentration in the environment and exposure time have an obvious relationship with the health effects of animals, the results and hypotheses cannot be fully applied to humans due to insufficient samples and the impossibility of effective human experiments. The positive correlation between exogenous formaldehyde and human health hazards cannot be concluded. Formaldehyde is not necessarily the basic reason of cause of nasopharyngeal carcinoma, leukemia, and reproductive defects (Marshall 1987; Vincent et al. 2004). Through the inhalation to labeling formaldehyde, the results show that formaldehyde has less or no effect on the distal body tissues such as bone marrow, liver, and kidney (Kang et al. 2021). When ADH5 and FANCD2 are deficient or defective, the formaldehyde hazards are increased, which indicates that gene defects may be the main pathogeny. Meanwhile, health hazards are closely related to other indoor air contaminants and lifestyle and health habits. The results of numerous studies on the health hazards of formaldehyde are basically based on the results of animal experiments and epidemiological research of human diseases, or some cases of mistaken ingestion of formaldehyde. Because of the great difference between humans and animals, and the inability of effective tests on human beings, it is impossible to study the hazards and mechanism of formaldehyde to human health. In addition, many studies have not fully demonstrated the health hazards of formaldehyde and there is a lack of effective research on the human body, which is also the focus of controversy, and have different opinions (Bryson et al. 2003; Nielsen et al. 2017). But there is a consensus on the potential hazards of high concentration and long-term exposure. Therefore, it is not necessary to panic too much about formaldehyde, and it is important to take correct preventive measures to reduce indoor formaldehyde concentration and exposure time.

Discussion and Conclusions

Numerous studies have shown that formaldehyde has potential genotoxicity. Excessive formaldehyde has adverse effects on genome stability and normal cell functions, such as causing the human body to be unable to metabolize normally, leading to DNA damage, repair inhibition, and chromosome mutation. Long-term exposure to high concentrations of formaldehyde will increase the risk of nasopharyngeal carcinoma, leukemia, and reproductive defects. In order to reduce the concentration of formaldehyde in indoor air, it is necessary to accelerate the research on wood products without and with low formaldehyde. By controlling the production and degradation process of formaldehyde, the metabolic stability of formaldehyde in the body can be maintained and formaldehyde imbalance can be prevented.

At present, the research on reducing or eliminating formaldehyde emissions from wood-based panels mainly focuses on reducing the molar ratio of formaldehyde to urea, improving the hot-pressing process, adding formaldehyde scavengers, post-processing technology, and using an alternative adhesive. However, formaldehyde emissions cannot be completely eliminated. Therefore, it is necessary to further strengthen the research on reducing the formaldehyde emissions of wood-based panels and indoor formaldehyde removal technology to reduce indoor formaldehyde concentration. Meanwhile, the epidemiology of formaldehyde hazards, formaldehyde pathogenesis genes and damage repair mechanism should be studied systematically, which can help to develop gene drugs to remove excess formaldehyde and activate the damage gene repair mechanism and void the harm of formaldehyde to health in the future.

Declaration of Competing Interest

All authors confirm that there is no conflict of interest for this research work and publication of this paper.

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Article submitted: November 15, 2022; Peer review completed: December 31, 2022; Revised version received and accepted: January 5, 2023; Published: January 13, 2023.

DOI: 10.15376/biores.18.1.Gao